In humans, chronic use of cocaine is often associated with a binge-like, uncontrollable pattern of use with overall tolerance and acute withdrawal. This cocaine withdrawal is characterized by severe depressive symptoms combined with irritability, anxiety, and anhedonia, lasting several hours to several days that may be one of the major motivating factors in the maintenance of the cocaine-dependence cycle. We have observed that the expression of Syndecan-3, a proteoglycan previously implicated in feeding behavior, is dramatically increased in the hypothalamus during withdrawal in animals self-administering cocaine and it was significantly higher in animals with an escalating pattern of cocaine self-administration. The present CEBRA proposal is aimed at investigating the role of hypothalamic Syndecan in cocaine intake. To this aim we propose to use adeno-associated (AAV) viral vectors expressing Syndecan -1, a peripheral form of Syndecan that is not cleaved by brain proteases and mimics the overexpression of Syndecan-3; constitutively shed Syndecan-1 ectodomain; or small interfering RNAs (siRNA) targeting Syndecan-3. The effect of hypothalamic injection of these constructs will be studied on cocaine self-administration in animals with an escalating pattern of cocaine self-administration in comparison to animals that self-administer consistent low levels of cocaine. The elucidation of the neurobiological bases for the transition from non-dependent drug use to addiction is of crucial importance for the development of novel and more effective therapeutic approaches.